Although electroconvulsive therapy (ECT) is a highly effective and widely used treatment for severe depression, an optimum schedule of administration has never been definitively established. Available evidence strongly suggests that twice weekly treatments are effective; yet more frequent schedules involving a greater number of ECT's, continue to be used in many centers, particularly in the U.S.A. Severity of ECT-induced memory impairment has been shown to be cumulatively related to frequency and number of treatments. The reduction in both parameters which a twice weekly schedule permits, is therefore highly desirable provided that therapeutic benefit can be definitively shown to be unimpaired. The present protocol therefore calls for a random assignment, double-blind comparison, controlled by the use of simulated ECT between twice and three times weekly schedules of ECT administration. Clinical response and cognitive function will be serially rated during the 4 week acute treatment period and long-term effects during 6 month continuation therapy with lithium carbonate. The underlying hypothesis of this proposal is that the antidepressant action of ECT is time dependent, and is not accelerated by increasing the frequency of treatment administration beyond an optimum level. Biological effects relevant to antidepressant mechanisms should be induced by the least frequent schedule which is clinically effective. Two potentially important parameters will be studied in this context: (1) Preclinical studies have strongly implicated central serotonergic effects in the mechanism of action of antidepressant treatments including ECT. In the present protocol, the plasma prolactin response to fenfluramine will be used as a marker for changes in central serotonergic function induced by ECT. (2) A recent neurophysiological theory suggests that the induction, by ECT, of a central hypometabolic state, may underlie its antidepressant action. in the present protocol, seizure threshold increases which putatively reflect the ECT-induced neural hypometabolic state, will be serially monitored during the treatment course. The effects of twice and three times weekly ECT on both these parameters will be compared and correlated with treatment outome. The findings of this project are therefore likely to have important implications for the mechanism of action of ECT in addition to their potential impact on clinical practice.